A moderate form of osteogenesis imperfecta caused by compound heterozygous LEPRE1 mutations

Abstract

Osteogenesis imperfecta (OI) is a genetic disorder causing skeletal fragility, multiple fractures, and other extraskeletal manifestations. Most cases are caused by mutations in COL1A1 or COL1A2. Recent investigations have discovered several other autosomal recessive genes responsible for OI. Among these genes is LEPRE1, which is involved in post-translational modifications of collagen. To date, more than 40 LEPRE1 mutations have been described. One of these mutations is carried by 1.5% of West Africans and 0.4% of African Americans, and is associated with OI Type VIII. We describe the case of a five year old male with a moderate form of OI and compound heterozygous LEPRE1 mutations (c.1080 + 1G > T; c.1646 T > G, p.Met549Arg). He was diagnosed shortly after birth following a skeletal survey demonstrating multiple healing fractures as well as lower extremity deformity suggestive of remote fractures. He was then without a fracture until a calvarial fracture at 18 months of age, a femur fracture at 4 years and seven months and a second femur fracture at 5 years and 4 months. He walked at age 14 months and has been an active boy. Pamidronate infusions began at seven weeks of age and were discontinued at three years of age due to increased bone mineral density and absence of fractures. Type VIII OI typically causes a severe to lethal phenotype presenting at birth with severe osteopenia, congenital fractures and other clinical manifestations. Only a few individuals have survived to childhood. This case description serves to expand the clinical phenotyping of this recessive form of OI into the more moderate spectrum.

Osteogenesis imperfecta: Novel genetic variants and clinical observations from a clinical exome study of 54 Indian patients

“…LEPRE1 gene variants are perinatally lethal and severe, presenting as OI types II and III (Santana, Franzone, McGreal, Kruse, & Bober, 2018). We have identified two novel homozygous duplications, c.2131dup (p.Leu711Profs*19)(SCV000987189) and c.1980dup (p.Val661Serfs*33)(SCV000987190), producing a truncated protein.…”

“…The joint contractures were mainly in FKBP10 variants with isolated cases in BMP1, CRTAP, COL1A1, and COL1A2. The plot was generated using GenVisR Bioconductor package [Colour figure can be viewed at wileyonlinelibrary.com] LEPRE1 gene variants are perinatally lethal and severe, presenting as OI types II and III (Santana, Franzone, McGreal, Kruse, & Bober, 2018). We have identified two novel homozygous duplications, c.2131dup (p.Leu711Profs*19)(SCV000987189) and c.1980dup (p.Val661Serfs*33)(SCV000987190), producing a truncated protein.…”

Severe cases of osteogenesis imperfecta type VIII due to a homozygous mutation in P3H1 (LEPRE1) and review of the literature

“…Although the measurements were made using different equipment in different centers, a good response was obtained with >300% improvement. 10 Takagi et al also reported an OI type VIII case in which pamidronate treatment was started at 2 months of age. The patient developed very few fractures and presented a good response.…”

Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant

“…Moderate type 4 OI has been reported in cases of missense P3H1 variants; numerous cases were documented in Turkish and other OI cohorts [ 7 , 16 ]. Although it is tempting to assume that maintenance of protein expression can have a protective role in diminishing disease severity, it is important to note that missense P3H1 pathogenic variants have also been reported as a cause of type 3 OI [ 29 , 30 ].…”

“…Defects in collagen type I can also be caused by several genes affecting its regulation [ 4 ]; the prevalence of OI forms by recessive genes may be increased in isolated consanguineous populations [ 5 ]. Pathogenic variants in the prolyl 3-hydroxylase 1 ( P3H1 , OMIM#: 610339) gene were discovered in 2006 as a cause of severe recessive OI, genetic type VIII (OMIM#: 610915) [ 3 , 6 ]; although the clinical types 2 and 3 OI are commonly reported, milder cases also exist [ 7 ]. P3H1 codes for P3H1, which forms a heterotrimeric complex with the cartilage-associated protein (CRTAP) and cyclophilin B (PPIB); pathogenic variants in both of the latter are also associated with OI [ 8 , 9 ].…”